The HIV envelope glycoprotein precursor, gpl60, is cleaved into the mature forms, gp120 and gp41, by the cellular protease furin and furin-like proprotein convertases (PPCs). In this application, we will explore the potential of PPC inhibition as a therapy for HIV infection. The hypothesis to be tested is that anti-HIV effects of PPC inhibition can be obtained at levels that do not cause untoward side effects. This will be tested at both the cellular level and in intact animals. We will present evidence that stable, small molecule PPC inhibitors, hexa and nona-D-arginine (D6R and D9R), can inhibit the spread of HIV infection in tissue culture in concentrations that do not affect cellular processes, and in another model that D6R can be used in vivo to prevent the cleavage of pseudomonas exotoxin A and anthrax toxin. These studies suggest that D6R and D9R may be used to treat HIV infection. To study the effects of inhibiting PPCs on HIV infection, we propose two specific aims. 1. To test the efficacy of D6R and D9R on in vitro spread of HIV infection and Env processing. 2. To test PPC inhibitors in a SCID-mouse model of HIV infection. These studies have relevance for the development of antiviral therapies, as well as treatments for other conditions in which furin and PPC action plays a pathological role. These studies will also help elucidate basic processes by which HIV utilizes the cell it inhabits.